A 3-aroyl-2-arylbenzo[b]thiophene recently has been clinically evaluated for use in treating and/or preventing osteoporosis. Specifically, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, also known as raloxifene, has been clinically tested for such use. In addition to the ability to inhibit bone resorption and bone loss, this compound also is effective in lowering serum cholesterol levels. Interestingly, following oral administration, this compound is extensively conjugated to a glucuronidated form. See Lindstrom et al., Xenobiotica, 14(11), 841-847 (1984). This glucuronide conjugate displays significant antiestrogenic and antiuteronropic activity. In various tissues, the conjugated or glucuronidated form is converted to raloxifene in vivo. See Frolik, Am. Soc. Bone and Mineral Research(ASBMR), Tampa, Fla., Sep. 12-18 (1993).
A synthesis of the various glucuronidated forms was required to assign a chemical structure to the metabolically conjugated form of raloxifene. Small quantities of two different monoglucuronides of raloxifene, the 4'-glucuronide and the 6-glucuronide, were produced by biotransformation using NIH3T3 cells. See Frolik, Am. Soc. Bone and Mineral Research (ASBMR), Tampa, Fla., Sep. 12-18 (1993). This process was suitable for the preparation of chromatographic standards of the glucuronides; however, this process is not suitable for large-scale synthesis of these glucuronides. Large quantities of these glucuronides are needed to study the pharmacokinetics and toxicity of these compounds. Because the multi-step chemical routes for synthesizing these glucuronides produce these compounds in Low yields, an efficient biotransformation process is desired.
Glucuronides of anti-hypertensive compounds are prepared by biotransformation using a culture of Streptomyces sp. MA6751. These compounds are N2-tetrazoyl .beta.-glucuronides, wherein the glucuronidation occurs on the tetrazole group of the anti-hypertensive compound. See U.S. Pat. Nos. 5,057,522 and 5,085,922, and Chin et al., J. Antibiot., 46(1), 131-134 (1993).